title: The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis.
abstract: We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10021, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.forename: Eirini
authors.initials: E
authors.lastname: Bournazou
authors.forename: Pasquale
authors.initials: P
authors.lastname: Sansone
authors.forename: Marjan
authors.initials: M
authors.lastname: Berishaj
authors.forename: Sizhi Paul
authors.initials: SP
authors.lastname: Gao
authors.forename: Laura
authors.initials: L
authors.lastname: Daly
authors.forename: Jared
authors.initials: J
authors.lastname: Wels
authors.forename: Till
authors.initials: T
authors.lastname: Theilen
authors.forename: Selena
authors.initials: S
authors.lastname: Granitto
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhang
authors.forename: Jesse
authors.initials: J
authors.lastname: Cotari
authors.forename: Mary L
authors.initials: ML
authors.lastname: Alpaugh
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonafe
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Mario
authors.initials: M
authors.lastname: Taffurelli
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.forename: Gregoire
authors.initials: G
authors.lastname: Altan-Bonnet
authors.forename: Rosandra
authors.initials: R
authors.lastname: Kaplan
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nishimoto
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: C545606:AZD 1480; D015850:Interleukin-6; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D053616:Janus Kinase 3